Ultrasound contrast imaging

ABSTRACT

The invention provides a non-invasive method and apparatus for improved ultrasonic imaging and for measurement of ambient pressure, temperature or gas concentration using non-invasive ultrasound contrast imaging techniques.

This application claims the benefit of foreign priority pursuant to 35U.S.C. §§119 and 371 to PCT/GB98/00159, filed Jan. 19, 1998 andcorresponding application in Great Britain, 9701274.4, filed Jan. 22.1997, the disclosure of which are incorporated herein by reference.

The present invention relates to ultrasound contrast imaging methods andapparatus and more particularly to measurement of pressure and/ortemperature in a body.

In particular the invention provides non-invasive real timedetermination of temperature, pressure, gas concentration etc in theblood. This is extremely difficult to achieve in, for example, internalorgans and, for example, real time determination of temperature of aninternal organ during treatment can provide the physician with valuableinformation allowing enhanced treatment.

This enables local determination of organ perfusion and localdetermination of ambient pressure, temperature or gas concentration.

The inventive technique is substantially better than alternativetechniques to achieve the same objective since organ perfusionmeasurements require x-ray technology and ambient pressure and gascontent measurements respectively require a pressure catheter and ablood sample.

U.S. Pat. No. 5,456,257 discloses an ultrasonic diagnostic system whichdetects the presence of coated microbubble contrast agents in the bodyof a patient by transmitting ultrasonic energy which causes thedestruction of the coated microbubbles and detects the microbubbledestruction through phase insensitive detection and differentiation ofechoes received from two consecutive ultrasonic transmissions.

According to the present invention there is provided an ultrasoundcontrast imaging method comprising generating a first, relatively highpower, acoustic field for a first predetermined number of cycles, andfollowing a predetermined time delay generating a second relativelylower power acoustic field for a second predetermined number of cycles,said first predetermined acoustic field causing, in use, power enhancedscattering and said second predetermined acoustic field being below thethreshold for power enhanced scattering and causing scattering providinginformation about possible generated free gas bubbles.

Power enhanced scattering is defined as providing an acoustic pulse atan amplitude at least sufficient to cause a change in the acousticproperties of the region of interest to, for example, cause bubbles tobe released from the microcapsules.

Preferably the acoustic field has a frequency of 100 kHz to 10 MHz.

The present invention also provides apparatus for ultrasound contrastimaging comprising means for generating a first relatively high poweracoustic field for a first predetermined time period, timing means forgenerating a predetermined delay time, and means for generating a secondrelatively low power acoustic field for a second predetermined periodfollowing said predetermined delay time.

Preferably the apparatus comprises receiver means for receiving a signalin a period following the generation of the second relatively low poweracoustic field.

Preferably the means for generating a second relatively low poweracoustic field comprises further timing delay means for repeating saidlow power acoustic field after a further predetermined delay. Preferablythe apparatus includes signal receiver means for interrogating areceived signal during said further predetermined delay.

In a preferred embodiment the apparatus comprises time sequencing meansfor repetitively supplying a series of relatively low power acousticfields with a predetermined time delay interposed between eachrelatively low power acoustic field and including receiver means forreceiving and interrogating a received signal during each predeterminedtime delay.

Preferably the apparatus includes means for determining from thereceived signal whether any generated small bubbles are still presentand means for terminating said sequence of relatively low acoustic powersignals on determination that no small bubbles are present.

The apparatus also preferably includes means for selectively adjustingthe insonifying frequency of the acoustic field to adjust thedisappearance period of the generated free gas bubbles.

Embodiments of the present invention will now be described, by way ofexample with reference to the accompanying drawings in which:

FIG. 1 shows a frequency characteristic waveform of a first transducerwith two distinct peaks used in the present invention;

FIG. 2 shows a frequency characteristic of a second transducer with afirst frequency peak and a broadband part to generate a low frequencyultrasound field with a length, amplitude and a broadband part forreceiving the scattered original;

FIG. 3 shows a complex acoustic field waveform in accordance with thepresent invention;

FIGS. 4A,B and C shows scatter information graphs illustrating theeffects of increasing delay period At of the waveform of FIG. 3;

FIG. 4D illustrates the decreasing response with delay time Δt;

FIG. 5 illustrates a method of measuring ambient pressure with, as anexample, At set to 80 μsecs.

FIG. 6 shows a block diagram of an apparatus for generating andanalysing the waveform of FIG. 3;

FIG. 7 comprises a flow diagram showing the sequence of events for theapparatus of FIG. 6 in generating and analysing the waveform of FIG. 3;and

FIG. 8 shows a graph of scattered energy versus time for differentsurrounding pressures.

INTRODUCTION

The present invention provides an apparatus and a method of measuringeither pressure, temperature or gas concentration by a non-invasivetechnique.

The measurement of instantaneous pressure or temperature in, forexample, an internal organ of an animal is extremely difficult bynon-invasive techniques.

The present invention provides such an apparatus and method.

The general principle will be explained followed by specific examples.The animal is injected or otherwise supplied with a suspension ofmicrocapsules suspended in a suitable liquid, for example isotonicsterile saline, such as Isoton.

Suitable microcapsules include those disclosed as “Quantison”microcapsules by Andaris Limited, and described in WO92/18164 (U.S. Pat.No. 5,518,709), WO94/08627 and WO96/15814 (U.S. Ser. No. 08/676,344filed Jul. 19 1996), all of which are incorporated herein by reference.The microcapsules are made by spray-drying a solution of serum albuminto form hollow microcapsules generally of diameter 1 to 10 μm; forexample 90% may have a diameter of 1.0 to 9.0 μm or 1.0 to 6.0 μum, asmeasured in a Coulter Counter Multisizer II. However, any gas containingmicrocapsule, microsphere or microparticle which releases the gas onirradiation with a non-physiologically harmful dose of ultrasound may beused in the methods of the invention.

These microcapsules are full of air or other suitable gas and for thepurposes of the present invention it will be assumed that they are fullof air. The animal, for example a human, is preferably injected in ablood vessel such as a vein or an artery, depending on the region whichis to be studied. Organs to be studied include the heart, kidneys andliver.

The general principle of the present invention is that thesemicrocapsules are subjected to an acoustic field of high power. Thisfield causes the air within the microcapsules to be expelled therebyreleasing small free air bubbles.

These free small air bubbles are absorbed into the liquid at differentrates dependent on the pressure and also dependent on the temperature.If the pressure within a vessel is known or is constant then thetemperature can be measured.

If the microcapsules are filled with another gas then this will resultin a different signal and a different persistence resulting in moreinformation of the ambient (blood) parameters.

Thus for example if an internal organ is subjected to an increase intemperature for therapy application it is fairly important to know thetemperature and this can be measured using this technique if it isassumed that the pressure remains constant.

Similarly for other vessels the temperature can be assumed to beconstant and therefore the pressure can be measured.

The small free air bubbles reflect or scatter a very sensitive signalwhich is readily detected. Therefore their rate of disappearance intothe surrounding liquid is readily detectable and since the time takenfor total (say for example 90%) dissolution is dependent on pressure andtemperature this can be accurately measured.

Referring to the drawings, the apparatus comprises a transducer. Threedifferent types of transducer are possible for contrast imaging andthese may be provided as follows:

a1 A transducer using the fundamental resonance frequency and using theharmonics, especially the third harmonic.

a2 A transducer with two frequency peaks, e.g. one peak at 1 MHz and theother at 2 MHz. The peaks themselves are relatively small banded(20-30%), the sensitivity between the two peaks is relatively low(preferably below −10 dB below the peak sensitivities at 1 MHz). Thesensitivity at 1 and 2 MHz are more or less the same. Other combinationscan be provided too, for example 1.5 and 3 MHz, 2.5 and 5 MHz etc. Sucha transducer can be provided, for example, by adapting the ¼ λ layerespecially by choosing the right impedance.

An example of such a design is given in FIG. 1 the frequency responsebeing shown with two clear peaks at 1 and 2 MHz.

a3 A transducer with a single frequency peak, e.g. a peak at, forexample, 1 MHz and a broadband part at a centre frequency of, forexample, 2 MHz. The first peak is relatively small banded (20-30%), andis used for a sending circuit to generate a low frequency ultrasoundfield with a high amplitude. The second broadband part is used forreceiving the scattered signal. The main difference from transducer typea2 is that this transducer a3 is also suitable for imaging of tissue byusing oily the sensitivity part around 2 MHz. Other combinations can beprovided too, for example, 1.5 and 3 MHz, 2.5 and 5 MHz etc. Such atransducer can be developed, for example, by using two matching layers,the first one (close to the transducer) with a high impedance, e.g. 20MRayls (±10 MRayls), the second one with an impedance of 3 MRayls (±2MRayls).

An example of such a design is given in FIG. 2 the frequency responsebeing shown with one clear peak at 1 MHz and a broadband part around 2MHz.

b Procedure of Scanning

b1 For a phased array the peak acoustic pressure amplitude decreases forincreasing scanning angle. Normally this is compensated by an increasinggain of the receiving signal. For ultrasound contrast imaging usingpower enhanced scattering, compensation has to be carried out byincreasing the transmit signal as a function of the scanning angle. Thepeak acoustic pressure amplitude will be then independent of the scanangle, resulting in a uniform scattering.

c Determination of Ambient Parameters (like pressure, temperature, gasconcentration) is Achieved as Follows by.

c1 Generating an acoustic field as shown in FIG. 3 of a certainfrequency (100 kHz-10 MHz) with an acoustic peak amplitude above thethreshold for causing power enhanced scattering and a number of periodsbetween 1 and 20, followed by a delay (Δt) and then an acoustic fieldwith an acoustic amplitude below the threshold causing power enhancedscattering. The second complex causes scattering which gives informationabout the (possible) generated free gas bubbles, like the bubble sizes.This scatter information is dependent on the delay (Δt) and willdecrease to zero for an increasing delay, indicating the disappearanceof the free gas bubbles. Information includes the ambient temperature,pressure, gas concentration, and, by the diffusion constant, also thegas content of the free gas bubble. An example is shown in FIG. 4.

In a preferred example, the procedure is transmitting with a 1 MHztransducer and followed by transmitting and receiving with a 2 MHzbroadband transducer. The transmitting consists of two sineburst; one of1 MHz, and one of 2 MHz. In a preferred example, the first burst (A) hasan amplitude of 300 V or above (equal to about 0.6 Mpascal or above) andthe second burst (B) has an amplitude of for, for example ⅓ of the firstpulse, e.g. 100 V for the 300 V example. The second pulse amplitudeshould be such as not to cause any substantial release of bubbles. Theamplitude V1 and length of frequency of both bursts can be controlled.The delay between the two bursts is Δt. The used concentration is 60 μl1.0-6.0 μm of diameter spray-dried albumin microcapsules in 1.5 lIsoton.

Although the above power figures provide the desired effect for the saidmicrocapsules, it may be possible to achieve the power enhancedscattering with lower power values if the wall strength of themicrocapsules used is lower.

The time traces of the scattering caused by burst B as function of thedelay Δt are given in FIG. 4. The figures show the received signal asmeasured with a 2 MHz frequency and with a delay Δt in FIG. 4A is 1 ms,in FIG. 4B it is 10 ms and in FIG. 4C 20 ms. At t=zero the medium wasinsonified with a high acoustic signal of 1 MHz. As can be seen thesignal has disappeared after 20 ms (FIG. 4C).

The signal trace is alternatively shown in FIG. 4D which shows thedecrease of signal amplitude (y axis) with time (x axis).

The inventor has also found a relationship between disappearance rateand insonifying frequency. Sensing the disappearance or appearance ofthe released free bubble can be used for imaging.

Experimental data shows the following disappearance rates for theinsonifying frequencies of 0.5, 1 and 2.5 MHz.

Insonifying Insonifying freq 0.5 MHZ freq. 1 MHZ Insonifying freq. 2.25MHZ approx. 20 ms approx. 10 ms approx 2 ms

c2 An exemplary method to measure the ambient pressure is given in FIG.5.

The delay Δt is set to 80 μs. The used concentration is 100 μl“Quantison” microcapsules in 1.5 l Isoton. Amplitude A was set to 300 V(0.51 MPascal), B to 100 V (0.17 MPascal). The insonify frequency is 1MHz. As receiver a broadband transducer of 10 MHz is used. Measurementsare made before (top panel); during (middle panel) and after (bottompanel). 160 mmHg overpressure is applied.

During overpressure, decreases of the higher harmonics were measured,together with a shift of the first harmonic, which were restored afterreleasing the overpressure. This provides a method for measuring theambient pressure providing other parameters, e.g. temperature, are knownor are constant.

In the fluid of interest, encapsulated air bubbles (Quantison, AndarisLtd., Nottingham, UK) are injected with optimal concentration. A lowfrequency, high acoustic amplitude burst (0.5 Mhz, 1.8 MPa, 10 μs) istransmitted to excite the microspheres and to generate free air bubbles.The disappearance rate of the released air bubbles is determined byusing a high frequency, low acoustic amplitude, broad band pulses (10MHz, 25 kPa, 100% at the −20 dB level, Pulse Repetition Frequency of 1.6kHz). Reproducible results show significant differences betweenpersistence of bubbles as function of ambient pressures (50, 100, 150and 200 mmHg).

FIG. 8 shows a graph illustrating the scattered energy of released airbubbles as a function of time for four different surrounding pressures.The x axis represents time in milliseconds and the y axis energy indecibels.

The first solid line represents the scattered energy of released airbubbles at an ambient surrounding pressure. The second dotted linerepresents 50 mm Hg pressure, the third dash—dotted 100 mm Hg and thefourth dotted line 200 mm Hg.

A base reference energy level may be set at −55 dB.

It may be seen that the graphs for 0 (ambient) 50, 100 and 200 mm Hgcross this reference level at 33, 29, 26 and 18 millisecs., therebyenabling the pressure to be measured by extrapolation if between theselevels.

The disappearance rates in Isoton and degassed Isoton were found to varysubstantially. Transmitting high acoustic power with a burst of 1 MHz,transmitting and receiving (at a low acoustic power) with 10 MHztransducer the following results were achieved.

saturated Isoton 10-12 ms degassed Isoton  2-3 ms

With reference now to FIG. 6, the apparatus for generating the waveformof FIG. 3 comprises a waveform generator 900 connected to a switch 902and a transducer 904 connected to receive and transmit signals via theswitch 902.

Signals from switch 902 are received by a receiver 906 the output ofwhich is fed to a signal analyser 908. The analyser 908 is connected toa frequency time and amplitude control circuit 910 which in turn isconnected to the waveform generator 900 to provide a control signal.

The operation of the apparatus to provide the waveform of FIG. 6 isshown in FIG. 7. From the start 1000 a region of interest 1002 isdetermined. The waveform generator 900 generates an acoustic line withhigh acoustic amplitude (1004 and this is then followed by a time delayof preferably between 1-10 μsec 1006).

An acoustic line with low acoustic amplitude is then generated 1008 bygenerator 900 and the signal received at receiver 906 is analysed fromthe region of interest (ROI) to determine the optimal frequency 1010.The signal is interrogated to determine if generated small bubbles arepresent 1012. If they are then the generator generates a further line1008. This further line is generated following a determination ofoptimal frequency 1014 and the line is generated after a second timedelay 1016. This process is repetitive. If no generated gas bubbles arepresent then the output is analysed to determine how long the bubblespersisted and their initial size 1018.

It is also possible to terminate the procedure on detection of a lowerlimit, e.g. −55 dB (see FIG. 8) and for the time of termination to beinterpolated to determine pressure, temperature or other characteristicsof a medium.

What is claimed is:
 1. An ultrasound contrast acoustic field generatingmethod characterised in that said method comprises generating a first,relatively high power, acoustic field (A) for a first predeterminednumber of cycles, and following a predetermined time delay (Δ_(t))generating a second relatively lower power acoustic field (B) for asecond predetermined number of cycles, said first predetermined acousticfield (A) causing, in use, power enhanced scattering of microcapsulesand said second predetermined acoustic field (B) being below thethreshold for power enhanced scattering and causing scattering providinginformation about possible generated free gas bubbles.
 2. An ultrasoundcontrast imaging method as claimed in claim 1 in which the acousticfield has a frequency of 100 kHz to 10 MHz.
 3. Apparatus for ultrasoundcontrast acoustic field generating characterised in that said apparatuscomprises means (900) for generating a first relatively high poweracoustic field for a first predetermined time period timing means (910)for generating a predetermined delay time, and means (900) forgenerating a second relatively low power acoustic field for a secondpredetermined period following said predetermined delay time. 4.Apparatus for ultrasound contrast imaging as claimed in claim 3comprising receiver means (906) for receiving a signal in a periodfollowing the generation of the second relatively low power acousticfield.
 5. Apparatus for ultrasound contrast imaging as claimed in claim4 including the means for generating a second relatively low poweracoustic field comprises further timing delay means for repeating saidlow power acoustic field after a further predetermined delay. 6.Apparatus for ultrasound contrast imaging as claimed in claim 5 in whichthe apparatus includes signal receiver means for interrogating areceived signal during said further predetermined delay.
 7. Apparatusfor ultrasound contrast imaging as claimed in claim 6 in which theapparatus comprises time sequencing means for repetitively supplying aseries of relatively low power acoustic fields with a predetermined timedelay interposed between each relatively low power acoustic field andincluding receiver means for receiving and interrogating a receivedsignal during each predetermined time delay.
 8. Apparatus for ultrasoundcontrast imaging as claimed in claim 5 in which the apparatus includesmeans for determining from the received signal whether any generatedsmall bubbles are still present and means for terminating said sequenceof relatively low acoustic power signals on determination that no smallbubbles are present.
 9. Apparatus for ultrasound contrast imaging asclaimed in claim 5 in which the apparatus includes means for determiningfrom the received signal whether any generated small bubbles are stillpresent and means for terminating said sequence of relatively lowacoustic power signals on determination that only a lower limit ofbubbles is present, the time period since commencement of the loweracoustic power signals providing an indication of pressure, temperatureor other characteristic of the medium in which the small bubbles arepresent.
 10. Apparatus for ultrasound contrast imaging as claimed inclaim 8, said apparatus including means for selectively adjusting theinsonifying frequency of the acoustic field to thereby adjust thedisappearance period of the generated frequency bubbles.
 11. Aultrasound method for determining a characteristic of a body, the methodcomprising: (a) generating a first acoustic field at a first power; (b)releasing free gas bubbles from microspheres in response to (a); (c)generating a second acoustic field at a second power less than the firstpower at a predetermined time after (a); and (d) determining thecharacteristic as a function of a response of the free gas bubbles tothe second acoustic field.
 12. The method of claim 11 wherein (d)comprises determining a pressure.
 13. The method of claim 11 wherein (d)comprises determining a temperature.
 14. The method of claim 11 furthercomprising (e) repeating (c) wherein (d) comprises determining thecharacteristic as a function of time and (e).
 15. The method of claim 11wherein (d) comprises determining the characteristic as a function ofthe predetermined time.